The overall goal of the Animal Models Core is to support all programs of the IPCAVD by performing immunization studies in CH58 unmutated common ancestor (UCA) VH + VL knock-in (KI) mice and rhesus macaques, with ALVAC-C vCP2438 prime and modified mRNA encoding trivalent mosaic gp120s for induction of polyfunctional anti-HIV-1 non-neutralizing antibodies (NNAbs) (Project 1, Aims 2 and 3), and by overseeing toxicity studies using CGMP clinical trials material (CTM) mRNAs in collaboration with Project 2. This work will be facilitated by recent innovative advances made in a number of complementing areas, including the development of novel SHIV constructs expressing transmitted/founder HIV-1 envelopes, well-tolerated adjuvants that substantially increase the immunogenicity of HIV-1 envelope protein immunogens and induce T follicular helper cell (Tfh) responses, technology for reproducibly generating envelope-specific monoclonal antibodies from immunized macaques, and use of the new CH58 VH and VL knock-in mouse that expresses one of the NNAb ADCC-mediating antibodies from RV144, CH58 V2 antibody. The Specific Aims of this Animal Models Core will include: Aim 1. Perform immunization studies in CH58 unmutated common ancestor (UCA) homozygous (hom)/heterozygous (het) VH + VL knock-in (KI) mice ALVAC-C vCP2438 prime and modified mRNA encoding trivalent mosaic gp120s in Project 1, Aim 2. Aim 2. Perform immunization studies with ALVAC-C vCP2438 prime and boosting with and boosting with ALVAC-C plus modified mRNA encoding trivalent mosaic gp120s mRNAs in rhesus macaques (RMs) (Project 1, Aim 3). Aim 3. Perform immunization studies in CH58 UCA hom/het VH + VL KI mice to confirm CGMP clinical trials materials immunogenicity, and oversee toxicity studies of ALVAC-C + CGMP mRNAs in collaboration with Project 2.